VPS51-Related Pontocerebellar Hypoplasia-CDG

Mendelian MONDO:0032831 Pathograph 4 Show in embeddings browser Neurodevelopmental Disorder Pontocerebellar Hypoplasia congenital disorder of glycosylation type II

VPS51-related pontocerebellar hypoplasia-CDG is a rare autosomal recessive neurodevelopmental and neurometabolic disorder caused by biallelic VPS51 variants. VPS51 encodes the shared GARP/EARP tethering-complex subunit needed for endosome-derived carrier fusion at the trans-Golgi network and recycling endosomes. Patient cells show reduced assembled GARP/EARP complexes, altered mannose-6-phosphate receptor distribution, lysosomal swelling, and abnormal cellular and serum glycoprotein glycosylation. Reported individuals have severe developmental delay or intellectual disability, microcephaly, epilepsy, hypotonia, thin corpus callosum or pontocerebellar abnormalities, failure to thrive, and variable hepatic, hearing, feeding, and vision involvement.

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1
Inheritance
4
Pathophys.
12
Phenotypes
4
Pathograph
1
Genes
1
Deep Research
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
vesicular trafficking
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported individuals carry biallelic VPS51 variants, including compound heterozygous and homozygous alleles.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30624672 SUPPORT Human Clinical
"By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a 6-year-old patient"
The initial report identified compound heterozygous VPS51 variants in an affected child.
PMID:40565173 SUPPORT Human Clinical
"we present two siblings with a novel homozygous variant in VPS51 (Vacuolar protein sorting 51) gene (c.1511C>T; p.Thr504Met)"
A later sibling report supports biallelic inherited VPS51 disease.
⚙

Pathophysiology

4
VPS51 GARP/EARP tethering-complex deficiency
Biallelic VPS51 variants reduce functional assembly of both GARP and EARP complexes. This impairs tethering/fusion of endosome-derived transport carriers at the trans-Golgi network and recycling endosomes.
VPS51 hgnc:1172 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VPS51 (hgnc:1172). hgnc:1172 is a gene from the HUGO Gene Nomenclature Committee.
vesicle-mediated transport GO:0016192 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vesicle-mediated transport (GO:0016192). GO:0016192 is a biological process from the Gene Ontology. ↓ DECREASED retrograde transport, endosome to Golgi GO:0042147 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retrograde transport, endosome to Golgi (GO:0042147). GO:0042147 is a biological process from the Gene Ontology. ↓ DECREASED
Golgi apparatus GO:0005794 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Golgi apparatus (GO:0005794). GO:0005794 is an anatomical location from the Gene Ontology.
Downstream
Endosome-Golgi cargo-sorting failure Reduced GARP/EARP assembly alters endosome-derived cargo sorting, including mannose-6-phosphate receptor distribution.
Show evidence (2 references)
PMID:30624672 SUPPORT In Vitro
"Consequently, skin fibroblasts from the patient have reduced levels of fully assembled GARP and EARP complexes."
Patient fibroblasts directly show reduced assembled tethering complexes downstream of VPS51 variants.
PMID:30624672 SUPPORT Other
"At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments."
The report defines the relevant vesicle-fusion role of the VPS51-containing complexes.
Endosome-Golgi cargo-sorting failure
Impaired VPS51-containing tethering disrupts recycling or sorting of endosome-derived cargo to the Golgi and lysosomal system, producing endolysosomal stress in patient cells.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
retrograde transport, endosome to Golgi GO:0042147 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retrograde transport, endosome to Golgi (GO:0042147). GO:0042147 is a biological process from the Gene Ontology. ↓ DECREASED lysosome organization GO:0007040 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal lysosome organization (GO:0007040). GO:0007040 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Abnormal cellular and serum glycoprotein glycosylation
Show evidence (2 references)
PMID:30624672 SUPPORT In Vitro
"Furthermore, a fraction of the patient's fibroblasts exhibits swelling of lysosomes."
Lysosomal swelling in patient fibroblasts supports downstream endolysosomal dysfunction.
PMID:40565173 SUPPORT In Vitro
"Proteomic profiling revealed 585 differentially expressed proteins, indicating disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism."
Proteomics in VPS51 patient fibroblasts extends the cellular mechanism to vesicular, lysosomal, and metabolic pathway disruption.
Abnormal cellular and serum glycoprotein glycosylation
GARP dysfunction impairs retention and stability of Golgi glycosylation machinery, producing abnormal N-linked and O-linked glycoprotein processing in the VPS51 disease context.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL protein O-linked glycosylation GO:0006493 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein O-linked glycosylation (GO:0006493). GO:0006493 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:34161137 SUPPORT In Vitro
"In summary, we have demonstrated that the GARP-KO human cells have defects in Golgi processing of N- and O-linked oligosaccharides."
GARP loss in human cells produces combined Golgi N- and O-glycan processing defects, matching the VPS51-associated CDG readout.
Neurologic and multisystem dysfunction
The cellular trafficking and glycosylation defects are associated with a severe neurodevelopmental syndrome with pontocerebellar, seizure, feeding, growth, hepatic, sensory, and hypotonia manifestations.
Show evidence (2 references)
PMID:30624672 SUPPORT Human Clinical
"severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features."
The initial case report summarizes the multisystem phenotype associated with biallelic VPS51 variants.
PMID:40565173 SUPPORT Human Clinical
"exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia."
The sibling report broadens the reported neurologic and multisystem phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for VPS51-Related Pontocerebellar Hypoplasia-CDG Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"microcephaly, hearing loss, and dysphagia."
The sibling report explicitly lists dysphagia.
Ear 1
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"microcephaly, hearing loss, and dysphagia."
The sibling report explicitly lists hearing loss.
Head and Neck 2
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia."
The sibling report explicitly lists microcephaly.
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"lower extremity edema and dysmorphic features."
The cached abstract reports dysmorphic features; HPO maps dysmorphic facial features to abnormal facial shape.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"microcephaly, hypotonia, epilepsy"
The original report explicitly lists hypotonia.
Nervous System 2
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"severe global developmental delay"
The initial patient was reported with severe global developmental delay.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"hypotonia, epilepsy, cortical vision impairment"
Epilepsy is included in the original VPS51 disease report.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"pontocerebellar abnormalities, failure to thrive, liver dysfunction"
The initial case report explicitly includes failure to thrive.
Other 4
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40565173 SUPPORT Human Clinical
"developmental delay, a thin corpus callosum, severe intellectual disability"
The sibling report explicitly includes thin corpus callosum.
Cerebral visual impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"epilepsy, cortical vision impairment, pontocerebellar abnormalities"
Cortical vision impairment is represented by the HPO cerebral visual impairment term.
Abnormality of the liver HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the liver (HP:0001392). HP:0001392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"failure to thrive, liver dysfunction, lower extremity edema"
Liver dysfunction is captured with the generic HPO liver abnormality term because the cached abstract does not specify a narrower hepatic feature.
Pedal edema HP:0010741 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pedal edema (HP:0010741). HP:0010741 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30624672 SUPPORT Human Clinical
"liver dysfunction, lower extremity edema and dysmorphic features."
Lower-extremity edema maps to the HPO pedal edema term.
🧬

Genetic Associations

1
VPS51 biallelic pathogenic variants (Loss of function mutation)
Gene: VPS51 hgnc:1172 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VPS51 (hgnc:1172). hgnc:1172 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30624672 SUPPORT Human Clinical
"The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome."
This supports a pathogenic VPS51 allele with severe protein instability.
PMID:30624672 SUPPORT In Vitro
"the other mutant allele produces a protein with a single amino acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits."
This supports impaired tethering-complex assembly as the effect of the second VPS51 allele.
🗃️

External Assertions

1
{ }

Source YAML

click to show 
name: VPS51-Related Pontocerebellar Hypoplasia-CDG
creation_date: "2026-07-06T12:00:00Z"
category: Mendelian
description: >-
  VPS51-related pontocerebellar hypoplasia-CDG is a rare autosomal recessive
  neurodevelopmental and neurometabolic disorder caused by biallelic VPS51
  variants. VPS51 encodes the shared GARP/EARP tethering-complex subunit needed
  for endosome-derived carrier fusion at the trans-Golgi network and recycling
  endosomes. Patient cells show reduced assembled GARP/EARP complexes, altered
  mannose-6-phosphate receptor distribution, lysosomal swelling, and abnormal
  cellular and serum glycoprotein glycosylation. Reported individuals have
  severe developmental delay or intellectual disability, microcephaly, epilepsy,
  hypotonia, thin corpus callosum or pontocerebellar abnormalities, failure to
  thrive, and variable hepatic, hearing, feeding, and vision involvement.
disease_term:
  preferred_term: VPS51-related pontocerebellar hypoplasia-CDG
  term:
    id: MONDO:0032831
    label: pontocerebellar hypoplasia, type 13
parents:
- Neurodevelopmental Disorder
- Pontocerebellar Hypoplasia
- congenital disorder of glycosylation type II
synonyms:
- VPS51-related neurodevelopmental disorder
- VPS51 deficiency
- VPS51-related GARP/EARP complex dysfunction
- pontocerebellar hypoplasia-CDG due to VPS51 deficiency
notes: >-
  Ontology anchor, corrected 2026-08-20. This entry previously carried no
  disease_term on the basis that no exact MONDO class existed. That was wrong:
  MONDO:0032831 "pontocerebellar hypoplasia, type 13" xrefs OMIM:618606 - the
  same OMIM number this entry was seeded from - and records VPS51 (HGNC:1172)
  as its causal gene via RO:0004003. It is bound here. The earlier audit
  correctly rejected PCH1A, which is a VRK1 anterior-horn-cell disorder, but
  did not go on to check the numbered PCH series past it.

  One caveat the binding does not resolve. MONDO:0032831 is classified under
  MONDO:0020135 pontocerebellar hypoplasia, not under MONDO:0015286 congenital
  disorder of glycosylation, so this entry is a member of the
  Congenital_Disorders_of_Glycosylation grouping without being a MONDO
  descendant of the grouping's mapped class. That is an upstream
  classification gap rather than a curation error here: patient cells show
  abnormal cellular and serum glycoprotein glycosylation, which is why the name
  carries the CDG suffix and why the entry conforms to the CDG module. A MONDO
  request to add the CDG parent to MONDO:0032831 would be the right follow-up,
  and is a smaller ask than the new-term request previously assumed to be
  needed.
external_assertions:
- name: OMIM VPS51-related pontocerebellar hypoplasia-CDG record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618606
  description: >-
    OMIM phenotype identifier supplied by WP-068 for VPS51-related
    pontocerebellar hypoplasia-CDG.
classifications:
  icimd_category:
  - classification_value: vesicular_trafficking
    notes: >-
      WP-068 classification 19.6.67.01: Complex Molecule and Organelle
      Metabolism, disorders of organelle biogenesis, dynamics and interactions,
      disorders of vesicular trafficking.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported individuals carry biallelic VPS51 variants, including compound
    heterozygous and homozygous alleles.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By exome sequencing, we have identified compound heterozygous mutations in
      the gene encoding the shared GARP/EARP subunit VPS51 in a 6-year-old
      patient
    explanation: >-
      The initial report identified compound heterozygous VPS51 variants in an
      affected child.
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we present two siblings with a novel homozygous variant in VPS51 (Vacuolar
      protein sorting 51) gene (c.1511C>T; p.Thr504Met)
    explanation: >-
      A later sibling report supports biallelic inherited VPS51 disease.
pathophysiology:
- name: VPS51 GARP/EARP tethering-complex deficiency
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  description: >-
    Biallelic VPS51 variants reduce functional assembly of both GARP and EARP
    complexes. This impairs tethering/fusion of endosome-derived transport
    carriers at the trans-Golgi network and recycling endosomes.
  genes:
  - preferred_term: VPS51
    term:
      id: hgnc:1172
      label: VPS51
  biological_processes:
  - preferred_term: vesicle-mediated transport
    modifier: DECREASED
    term:
      id: GO:0016192
      label: vesicle-mediated transport
  - preferred_term: retrograde transport, endosome to Golgi
    modifier: DECREASED
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consequently, skin fibroblasts from the patient have reduced levels of
      fully assembled GARP and EARP complexes.
    explanation: >-
      Patient fibroblasts directly show reduced assembled tethering complexes
      downstream of VPS51 variants.
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At these locations, GARP and EARP function to promote the fusion of
      endosome-derived transport carriers with their corresponding compartments.
    explanation: >-
      The report defines the relevant vesicle-fusion role of the VPS51-containing
      complexes.
  downstream:
  - target: Endosome-Golgi cargo-sorting failure
    causal_link_type: DIRECT
    description: >-
      Reduced GARP/EARP assembly alters endosome-derived cargo sorting, including
      mannose-6-phosphate receptor distribution.
    evidence:
    - reference: PMID:30624672
      reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the patient's fibroblasts display altered distribution of the
        cation-independent mannose 6-phosphate receptor, which normally sorts
        acid hydrolases to lysosomes.
      explanation: >-
        Patient fibroblast imaging directly supports altered cargo receptor
        distribution.
- name: Endosome-Golgi cargo-sorting failure
  description: >-
    Impaired VPS51-containing tethering disrupts recycling or sorting of
    endosome-derived cargo to the Golgi and lysosomal system, producing
    endolysosomal stress in patient cells.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: retrograde transport, endosome to Golgi
    modifier: DECREASED
    term:
      id: GO:0042147
      label: retrograde transport, endosome to Golgi
  - preferred_term: lysosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007040
      label: lysosome organization
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, a fraction of the patient's fibroblasts exhibits swelling of
      lysosomes.
    explanation: >-
      Lysosomal swelling in patient fibroblasts supports downstream
      endolysosomal dysfunction.
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Proteomic profiling revealed 585 differentially expressed proteins,
      indicating disruptions in vesicular trafficking, lysosomal function, and
      mitochondrial metabolism.
    explanation: >-
      Proteomics in VPS51 patient fibroblasts extends the cellular mechanism to
      vesicular, lysosomal, and metabolic pathway disruption.
  downstream:
  - target: Abnormal cellular and serum glycoprotein glycosylation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired GARP-dependent maintenance of Golgi glycosylation enzymes
    evidence:
    - reference: PMID:34161137
      reference_title: "The Golgi-associated retrograde protein (GARP) complex plays an essential role in the maintenance of the Golgi glycosylation machinery."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        a patient with a neurodevelopmental disorder caused by mutations in the
        VPS51 subunit of GARP and EARP was shown to exhibit abnormal
        glycosylation of cellular and serum glycoproteins
      explanation: >-
        The GARP glycosylation study explicitly connects VPS51 disease to
        abnormal cellular and serum glycoprotein glycosylation.
- name: Abnormal cellular and serum glycoprotein glycosylation
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    GARP dysfunction impairs retention and stability of Golgi glycosylation
    machinery, producing abnormal N-linked and O-linked glycoprotein processing
    in the VPS51 disease context.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  chemical_entities:
  - preferred_term: N-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59520
      label: N-glycan
  - preferred_term: O-glycan
    modifier: ABNORMAL
    term:
      id: CHEBI:59521
      label: O-glycan
  evidence:
  - reference: PMID:34161137
    reference_title: "The Golgi-associated retrograde protein (GARP) complex plays an essential role in the maintenance of the Golgi glycosylation machinery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In summary, we have demonstrated that the GARP-KO human cells have defects
      in Golgi processing of N- and O-linked oligosaccharides.
    explanation: >-
      GARP loss in human cells produces combined Golgi N- and O-glycan
      processing defects, matching the VPS51-associated CDG readout.
- name: Neurologic and multisystem dysfunction
  description: >-
    The cellular trafficking and glycosylation defects are associated with a
    severe neurodevelopmental syndrome with pontocerebellar, seizure, feeding,
    growth, hepatic, sensory, and hypotonia manifestations.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe global developmental delay, microcephaly, hypotonia, epilepsy,
      cortical vision impairment, pontocerebellar abnormalities, failure to
      thrive, liver dysfunction, lower extremity edema and dysmorphic features.
    explanation: >-
      The initial case report summarizes the multisystem phenotype associated
      with biallelic VPS51 variants.
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      exhibiting developmental delay, a thin corpus callosum, severe
      intellectual disability, epilepsy, microcephaly, hearing loss, and
      dysphagia.
    explanation: >-
      The sibling report broadens the reported neurologic and multisystem
      phenotype.
phenotypes:
- category: Neurological
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Severe developmental delay is a core reported feature.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe global developmental delay"
    explanation: >-
      The initial patient was reported with severe global developmental delay.
- category: Neurological
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  description: >-
    Microcephaly is reported in the original patient and later affected
    siblings.
  evidence:
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delay, a thin corpus callosum, severe intellectual
      disability, epilepsy, microcephaly, hearing loss, and dysphagia.
    explanation: >-
      The sibling report explicitly lists microcephaly.
- category: Neurological
  name: Seizures
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Epilepsy is reported in VPS51-related disease.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia, epilepsy, cortical vision impairment"
    explanation: >-
      Epilepsy is included in the original VPS51 disease report.
- category: Neurological
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Hypotonia is part of the original presentation.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, hypotonia, epilepsy"
    explanation: >-
      The original report explicitly lists hypotonia.
- category: Neurological
  name: Thin corpus callosum
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  description: >-
    Thin corpus callosum was reported in later affected siblings.
  evidence:
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay, a thin corpus callosum, severe intellectual disability"
    explanation: >-
      The sibling report explicitly includes thin corpus callosum.
- category: Growth
  name: Failure to thrive
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  description: >-
    Failure to thrive is reported in the original case.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pontocerebellar abnormalities, failure to thrive, liver dysfunction"
    explanation: >-
      The initial case report explicitly includes failure to thrive.
- category: Neurological
  name: Cerebral visual impairment
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  description: >-
    Cortical visual impairment was reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "epilepsy, cortical vision impairment, pontocerebellar abnormalities"
    explanation: >-
      Cortical vision impairment is represented by the HPO cerebral visual
      impairment term.
- category: Hepatic
  name: Abnormality of the liver
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  description: >-
    Liver dysfunction was reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "failure to thrive, liver dysfunction, lower extremity edema"
    explanation: >-
      Liver dysfunction is captured with the generic HPO liver abnormality term
      because the cached abstract does not specify a narrower hepatic feature.
- category: Fluid regulation
  name: Pedal edema
  phenotype_term:
    preferred_term: Pedal edema
    term:
      id: HP:0010741
      label: Pedal edema
  description: >-
    Lower-extremity edema was reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver dysfunction, lower extremity edema and dysmorphic features."
    explanation: >-
      Lower-extremity edema maps to the HPO pedal edema term.
- category: Craniofacial
  name: Abnormal facial shape
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  description: >-
    Dysmorphic features were reported in the original VPS51 case.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lower extremity edema and dysmorphic features."
    explanation: >-
      The cached abstract reports dysmorphic features; HPO maps dysmorphic
      facial features to abnormal facial shape.
- category: Hearing
  name: Hearing impairment
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  description: >-
    Hearing loss was reported in later affected siblings.
  evidence:
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, hearing loss, and dysphagia."
    explanation: >-
      The sibling report explicitly lists hearing loss.
- category: Feeding
  name: Dysphagia
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  description: >-
    Dysphagia was reported in later affected siblings.
  evidence:
  - reference: PMID:40565173
    reference_title: "From Gene to Pathways: Understanding Novel Vps51 Variant and Its Cellular Consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly, hearing loss, and dysphagia."
    explanation: >-
      The sibling report explicitly lists dysphagia.
genetic:
- name: VPS51 biallelic pathogenic variants
  association: Loss of function mutation
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: VPS51
    term:
      id: hgnc:1172
      label: VPS51
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    Reported pathogenic alleles include compound heterozygous variants with an
    unstable frameshift product and a missense protein that assembles less
    efficiently into GARP/EARP, and a homozygous p.Thr504Met sibling variant.
  evidence:
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation in one allele causes a frameshift that produces a longer but
      highly unstable protein that is degraded by the proteasome.
    explanation: >-
      This supports a pathogenic VPS51 allele with severe protein instability.
  - reference: PMID:30624672
    reference_title: "A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the other mutant allele produces a protein with a single amino acid
      substitution that is stable but assembles less efficiently with the other
      GARP/EARP subunits.
    explanation: >-
      This supports impaired tethering-complex assembly as the effect of the
      second VPS51 allele.
📚

References & Deep Research

Deep Research

1
VPS51-Related Pontocerebellar Hypoplasia-CDG Deep Research Fallback ▸

VPS51-Related Pontocerebellar Hypoplasia-CDG Deep Research Fallback

Scope

No provider-generated deep research artifact was present on the WP-068 branch. This fallback audit documents the literature scope used to curate and review the VPS51-related entry from cached PubMed references.

Evidence Scope Used For Curation

  • PMID:30624672 for the original biallelic VPS51 case, reduced assembled GARP/EARP complexes, mannose-6-phosphate receptor redistribution, lysosomal swelling, and the clinical phenotype including developmental delay, microcephaly, hypotonia, epilepsy, cortical visual impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema, and dysmorphic features.
  • PMID:40565173 for later affected siblings with a homozygous VPS51 variant, fibroblast proteomics showing vesicular, lysosomal, and mitochondrial pathway disruption, and additional phenotypes including thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia.
  • PMID:34161137 for the mechanistic link between GARP disruption and abnormal cellular and serum glycoprotein glycosylation.

Curation Conclusions

The supported model is biallelic VPS51 dysfunction causing combined GARP/EARP tethering-complex deficiency. Patient-cell evidence supports impaired endosome-derived cargo sorting, lysosomal abnormalities, and downstream Golgi glycoprotein processing defects. The curated phenotype set should include the core neurologic and growth features plus sensory, hepatic, edema, dysmorphic, hearing, and swallowing features reported in the cached literature.